The primary objective of this proposal is to further evaluate the mechanism of lipid alterations following portacaval shunting in the pig. Four approaches are planned following portacaval shunt: 1) Evaluation of hepatic cholesterol and lipid synthesis in the Yucatan miniature swine, 2) evaluation of the effects of hormones on hepatic lipid synthesis, 3) evaluation of cholesterol degradation, 4) evaluation of the ability of the shunt to reverse atherosclerosis. Portacaval shunt has been shown to be an effective means of lowering cholesterol levels in type IIA hyperlipoproteinemia patients. The physiologic mechanisms of postshunt lipid lowering are still poorly understood. This project is designed to evaluate cholesterol synthesis and degradation following shunt. Our initial studies in the New Zealand white pig have shown that cholesterol synthesis is lowered, and this will be confirmed using the Yucatan. Studies of cholesterol degradation following portacaval shunting have not yet been reported. Our previous techniques using the minipig will be ideal for these degradation studies. The project will evaluate hormonal replacement following shunting, in that insulin, glucagon or saline (controls) will be infused into the stub of the portal vein to determine if the previously described reduction in hepatic cholesterol synthesis is altered. After shunting, these hormones no longer perfuse the liver in high concentration, and it is hypothesized that this results in decreased lipoprotein and/or cholesterol synthesis. Thus, more will be learned about the normal physiologic control of hepatic cholesterol synthesis. Finally, pigs will be made atherosclerotic by feeding a high fat-high cholesterol diet. Some animals will then be shunted and some will be sham-operated. It is not yet known if portacaval shunt results in reversal of atherosclerosis concomitant with lipid lowering. If this occurs in the atherosclerotic pig, it may also occur in the human.